In order to break the cycle of intergenerational transmission from women alcoholics to their offspring, we need to identify the relevant mediating and moderating risk factors. This would make it possible to intervene in the lives of high-risk children before alcohol abuse becomes entrenched in their life-styles. Because we need a better understanding of how to identify those children at highest risk, offspring of parents with the most severe form of the disorder need to be studied. We have successfully identified a particularly severe form of alcoholism in women utilizing a double proband methodology which was first developed in our laboratory to select more severe cases of male alcoholism (e.g. early onset, high familial aggregation). During thee first five years of this award we identified 40 extended high-risk pedigrees, and among other goals achieved, successfully evaluated offspring from these pedigrees cross- sectionally. We compared these offspring to low-risk controls using neurophysiological indices associated with risk for alcoholism (primarily the amplitude of the P300). We also evaluated these offspring for psychopathological characteristics utilizing direct clinical interviews (consensus diagnoses based on a K-SADS interview separately with the child and the parent). We find: (1) significantly reduced P300 among these offspring of female alcoholics from high density families; and (2) significantly more psychopathology, both externalizing and internalizing. These effects are present even when only the mother is alcoholic and in the absence of drinking during pregnancy. The primary goal of the proposed renewal is to follow 200 high and low- risk offspring over the next five years. We will model: (1) age of onset for regular drinking, and (2) severity of psychopathology. In order to insure that the findings to date are robust, we will include an unscreened control group of offspring to be compared with our high-risk group and the screened low-risk group already available for follow-up. We have documented in several published studies, the presence of neurobiological risk factors (e.g. reduced amplitude of P300) in high- risk children. We suggest that these neurobiological indices may signal developmental delays for some children. These findings underscore the importance of utilizing these potential neurobiological markers prospectively and relate them to later development of alcohol dependence. The possible interplay between environmental variation and the neurobiological factors associated with high-risk status also suggests the need to assess this variation in the context of a longitudinal follow-up.